7YS6
Cryo-EM structure of the Serotonin 6 (5-HT6) receptor-DNGs-scFv16 complex
Summary for 7YS6
| Entry DOI | 10.2210/pdb7ys6/pdb |
| EMDB information | 34073 |
| Descriptor | 5-hydroxytryptamine receptor 6, Guanine nucleotide-binding protein G(I)/G(S)/G(T) subunit beta-1, Guanine nucleotide-binding protein G(I)/G(S)/G(O) subunit gamma-2, ... (6 entities in total) |
| Functional Keywords | gpcr, serotonin receptor, 5-ht6r, cryo-em, constitutive activity, membrane protein |
| Biological source | Homo sapiens (human) More |
| Total number of polymer chains | 5 |
| Total formula weight | 152647.27 |
| Authors | Zhao, Q.Y.,Wang, Y.F.,He, L.,Wang, S.,Cong, Y. (deposition date: 2022-08-11, release date: 2023-03-29, Last modification date: 2025-06-18) |
| Primary citation | He, L.,Zhao, Q.Y.,Qi, J.,Wang, Y.,Han, W.,Chen, Z.,Cong, Y.,Wang, S. Structural insights into constitutive activity of 5-HT 6 receptor. Proc.Natl.Acad.Sci.USA, 120:e2209917120-e2209917120, 2023 Cited by PubMed Abstract: While most therapeutic research on G-protein-coupled receptors (GPCRs) focuses on receptor activation by (endogenous) agonists, significant therapeutic potential exists through agonist-independent intrinsic constitutive activity that can occur in various physiological and pathophysiological settings. For example, inhibiting the constitutive activity of 5-HTR-a receptor that is found almost exclusively in the brain and mediates excitatory neurotransmission-has demonstrated a therapeutic effect on cognitive/memory impairment associated with several neuropsychiatric disorders. However, the structural basis of such constitutive activity remains unclear. Here, we present a cryo-EM structure of serotonin-bound human 5-HTR-Gs heterotrimer at 3.0-Å resolution. Detailed analyses of the structure complemented by comprehensive interrogation of signaling illuminate key structural determinants essential for constitutive 5-HTR activity. Additional structure-guided mutagenesis leads to a nanobody mimic Gαs for 5-HTR that can reduce its constitutive activity. Given the importance of 5-HTR for a large number of neuropsychiatric disorders, insights derived from these studies will accelerate the design of more effective medications, and shed light on the molecular basis of constitutive activity. PubMed: 36989299DOI: 10.1073/pnas.2209917120 PDB entries with the same primary citation |
| Experimental method | ELECTRON MICROSCOPY (3 Å) |
Structure validation
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